Onsolis

"Oct. 24, 2012 -- It is not a desired discussion for the doctor, and certainly not for the patient. But an overwhelming majority of people with advanced cancer are under the impression that the chemotherapy they are receiving will cure their disea"...

Onsolis

SIDE EFFECTS

Clinical Studies Experience

The safety of ONSOLIS has been evaluated in 306 opioid
tolerant patients with breakthrough cancer pain in the efficacy study and an
open-label safety study. The mean duration of therapy was 115 days, with 32
patients treated for more than 1 year.

The adverse reactions seen with ONSOLIS are typical
opioid side effects in a population with cancer. Frequently, opioid-associated
adverse reactions will cease or decrease in intensity with continued use of
ONSOLIS. Expect opioid side effects and manage them accordingly.

The most serious adverse reactions associated with all
opioids including ONSOLIS are respiratory depression (potentially leading to
apnea or respiratory arrest), circulatory depression, hypotension, and shock.
Follow all patients for symptoms of respiratory depression.

Because the clinical trials of ONSOLIS were designed to
evaluate safety and efficacy in treating patients with breakthrough pain
associated with cancer, all patients were also taking concomitant opioids, such
as sustained-release morphine, sustained-release oxycodone or transdermal
fentanyl, for their persistent cancer pain. The adverse event data presented
here reflect the actual percentage of patients experiencing each adverse event
among patients who received ONSOLIS for breakthrough cancer pain along with a
concomitant opioid for persistent cancer pain. There has been no attempt to
correct for concomitant use of other opioids, duration of ONSOLIS therapy, or
cancer-related symptoms. Adverse reactions are included regardless of severity.

Because clinical trials are conducted under widely
varying conditions, adverse event rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.

Table 1 lists, by maximum dose received, adverse
reactions with an overall frequency of 5% or greater that occurred during
titration. The ability to assign a dose-response relationship to these adverse
reactions is limited by the titration schedules used in these studies. Adverse
reactions are listed in descending order of frequency within each body system.

Table 1 : Adverse Reactions Which Occurred During
Titration at a Frequency of ≥ 5%

Table 2 : Adverse Reactions Which Occurred During
Long-Term Treatment at a Frequency of ≥ 5%

System Organ Class, Preferred Term, n (%)

ONSOLIS Dose (mcg)

Total
(N=213)

200
(N=23)

400
(N=59)

600
(N=79)

800
(N=91)

1200
(N=81)

> 1200
(N=28)

Gastrointestinal

Nausea

2 (9)

6 (10)

8 (10)

12(13)

26 (32)

4 (14)

56 (26)

Vomiting

1 (4)

5 (8)

9 (11)

8 (9)

23 (28)

3 (11)

45 (21)

Constipation

2 (9)

4 (7)

4 (5)

4 (4)

6 (7)

4 (14)

23(11)

Diarrhea

1 (4)

1 (2)

4 (5)

4 (4)

10 (12)

0

19 (9)

Dry mouth

1 (4)

4 (7)

3 (4)

2 (2)

3 (4)

1 (4)

14 (7)

Abdominal pain

0

0

3 (4)

1 (1)

7 (9)

1 (4)

11 (5)

General/administration site

Asthenia

0

6 (10)

3 (4)

8 (9)

7 (9)

4 (14)

28(13)

Fatigue

2 (9)

6 (10)

1 (1)

7 (8)

7 (9)

3 (11)

25(12)

Investigations

Weight decreased

3 (13)

0

2 (3)

5 (5)

5 (6)

1 (4)

15 (7)

Metabolism/nutrition

Dehydration

1 (4)

4 (7)

6 (8)

5 (5)

10 (12)

3 (11)

28(13)

Decreased appetite

0

4 (7)

4 (5)

6 (7)

2 (2)

2 (7)

18 (8)

Anorexia

2 (9)

1 (2)

3 (4)

4 (4)

6 (7)

1 (4)

17 (8)

Nervous system

Dizziness

2 (9)

4 (7)

2 (3)

3 (3)

10 (12)

2 (7)

23(11)

Headache

2 (9)

1 (2)

3 (4)

9 (10)

7 (9)

0

20 (9)

Somnolence

2 (9)

0

4 (5)

2 (2)

3 (4)

3 (11)

14 (7)

Psychiatric

Confusional state

1 (4)

0

4 (5)

4 (4)

6 (7)

4 (14)

18 (8)

Depression

0

3 (5)

1 (1)

4 (4)

7 (9)

3 (11)

18 (8)

Insomnia

0

2 (3)

2 (3)

3 (3)

4 (5)

2 (7)

12 (6)

Anxiety

1 (4)

1 (2)

2 (3)

3 (3)

3 (4)

1 (4)

11 (5)

Respiratory

Dyspnea

3 (13)

4 (7)

3 (4)

8 (9)

6 (7)

3 (11)

26 (12)

Cough

1 (4)

0

3 (4)

5 (5)

6 (7)

1 (4)

15 (7)

Vascular

Hypotension

0

3 (5)

3 (4)

1 (1)

3 (4)

1 (4)

11 (5)

In a mucositis study, a group
of patients (n=7) with Grade 1 oral mucositis and a matched group of control
patients (n=7) without oral mucositis were included in a clinical trial
designed to support the safety of ONSOLIS. The adverse event profile was
similar in both subsets of patients. There was no evidence that ONSOLIS caused
or worsened oral mucosal irritation or pain in either study group.

The duration of exposure to
ONSOLIS varied greatly, and included open-label and double-blind studies. The
adverse reactions listed below represent those that were reported by ≥ 1%
of patients from two clinical trials (the titration and post-titration periods)
while receiving ONSOLIS. Events are classified by system organ class.

DRUG INTERACTIONS

Fentanyl is metabolized mainly via the human CYP3A4
isoenzyme system; therefore potential interactions may occur when ONSOLIS is
given concurrently with agents that affect CYP3A4 activity.

The concomitant use of ONSOLIS with CYP3A4 inhibitors (e.g.,
indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole,
nefazodone, saquinavir, telithromycin, aprepitant, diltiazem, erythromycin,
fluconazole, grapefruit juice, verapamil, or cimetidine) may result in a
potentially dangerous increase in fentanyl plasma concentrations, which could
increase or prolong adverse drug effects and may cause potentially fatal
respiratory depression. Patients receiving ONSOLIS who begin therapy with, or
increase the dose of, CYP3A4 inhibitors should be carefully monitored for signs
of opioid toxicity over an extended period of time. Dosage increase should be
done conservatively [see WARNINGS AND PRECAUTIONS].

The concomitant use of ONSOLIS with CYP3A4 inducers (e.g.,
barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine,
oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St.
John's wort, or troglitazone) may result in a decrease in fentanyl plasma
concentrations, which could decrease the efficacy of ONSOLIS. Patients
receiving ONSOLIS who stop therapy with, or decrease the dose of, CYP3A4 inducers
should be monitored for signs of increased ONSOLIS activity and the dose of
ONSOLIS should be adjusted accordingly.

Drug Abuse And Dependence

Controlled Substance

Fentanyl is a Schedule II controlled substance that can
produce drug dependence of the morphine type. ONSOLIS may be subject to misuse,
abuse and addiction.

Abuse And Addiction

Manage the handling of ONSOLIS to minimize the risk of
abuse, including restriction of access and accounting procedures as appropriate
to the clinical setting and as required by law [seeHOW SUPPLIED and Storage
and Handling].

Concerns about abuse and addiction should not prevent the
proper management of pain. However, all patients treated with opioids require
careful monitoring for signs of abuse and addiction, because use of opioid
analgesic products carries the risk of addiction even under appropriate medical
use.

Addiction is a primary, chronic, neurobiologic disease,
with genetic, psychosocial, and environmental factors influencing its
development and manifestations. It is characterized by behaviors that include
one or more of the following: impaired control over drug use, compulsive use,
continued use despite harm, and craving. Drug addiction is a treatable disease,
utilizing a multidisciplinary approach, but relapse is common. “Drug-seeking”
behavior is very common in addicts and drug abusers.

Abuse and addiction are separate and distinct from
physical dependence and tolerance. Physicians should be aware that addiction
may not be accompanied by concurrent tolerance and symptoms of physical
dependence in all addicts. In addition, abuse of opioids can occur in the
absence of addiction and is characterized by misuse for nonmedical purposes,
often in combination with other psychoactive substances. Since ONSOLIS may be
abused for non-medical use, careful record keeping of prescribing information,
including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of patients, proper prescribing
practices, periodic reevaluation of therapy, and proper dispensing and storage
are appropriate measures that help to limit abuse of opioid drugs.

Healthcare professionals should contact their State
Professional Licensing Board, or State Controlled Substances Authority for
information on how to prevent and detect abuse of this product.

Dependence

Guide the administration of ONSOLIS by the response of
the patient.

Physical dependence is not ordinarily a concern when one
is treating a patient with chronic cancer pain, and fear of tolerance and
physical dependence should not deter using doses that adequately relieve the
pain.

Withdrawal also may be precipitated through the
administration of drugs with opioid antagonist activity, e.g., naloxone,
nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol,
buprenorphine, nalbuphine).

Physical dependence usually does not occur to a
clinically significant degree until after several weeks of continued opioid
usage. Tolerance, in which increasingly larger doses are required in order to
produce the same degree of analgesia, is initially manifested by a shortened
duration of analgesic effect, and subsequently, by decreases in the intensity
of analgesia.

Last reviewed on RxList: 1/26/2015
This monograph has been modified to include the generic and brand name in many instances.